5-(3&#39;-alkoxy or halo-propylidene)-dibenzo (a d)cyclohepta(1 4 6)triene - 10-carboxylic acid amides

ABSTRACT

DIBENZO(A,D)CYCLOHEPTA(1,4,6)TRIENES BEARING IN THE 5-POSITION, SUBSTITUENTS SUCH AS, FOR EXAMPLE, OXO-OR 3&#39;&#39;LOWER ALKOCYALKYLIDENE AN IN THE 10-POSITION, SUBSTITUENTS SUCH AS, FOR EXAMPLE, CARBONYL, THIOCARBONYL OR GUANYL RADICALS, FOR INSTANCE, 5-(3&#39;&#39;-LOWER ALKOXYPROPYLIDENE) - DIBENZO(A,D)CYCLOHEPTA(1,4,6)TRIENE 10 - CARBOXYLIC ACID DI-(LOWER ALKYL)AMIDES AND DIBENZO(A,D) CYCLOHEPTA (1,4,6) TRIEN-5-ONE 10 - CARBOXYLIC ACID CYCLIC AMIDES, PREPARED INTER ALIA, FROM 5-(3&#39;&#39;-LOWER ALKOXYPROPYLIDENE) - DIBENZO(A,D)CYCLOHEPTA(1,4,6)TRIENE 10CARBOXYLIC ACID, 10 - HALOCARBONYL - 5-(3&#39;&#39;LOWER ALKOXYPROPYLIDENE)DIBENZO(A,D)CYCLOHEPTA(1,4,6)TRIENE OR DIBENZO(A,D)CYCLOHEPTA(1,4,6)TRIENS-5 - ONE 10-CARBOXYLIC ACID HALIDE, ARE DESCRIBED. THE END PRODUCTS ARE USEFUL AS ANTIDEPRESSANTS.

United States Patent 5-(3-ALKOXY 0R HALO-PROPYLIDENE)-DIBENZO[a,d]CYCLOHEPTA[1,4,6]NE IO-CARBOXYL- IC ACID AIVHDES Gerald Rey-Belletand Hans Spiegelberg, Basel, Switzerland, assignors to Hotfmann-La RocheInc., Nutley,

N0 Drawing. Continuation-impart of application Ser. No. 431,981, Feb.11, 1965. This application Sept. 12, 1968, Ser. No. 759,499

Claims priority, application Switzerland, Feb. 18, 1964,

1,969/64; Dec. 4, 1964, 15,709/64 Int. Cl. C07c 103/30 US. Cl. 260-559 R5 Claims ABSTRACT OF THE DISCLOSURE Dibenzo[a,d]cyclohepta[1,4,6]trienesbearing in the 5-position, substituents such as, for example, oxoor 3-lower alkoxyalkylidene and in the 10-position, substituents such as, forexample, carbonyl, thiocarbonyl or guanyl radicals, for instance,5-(3'-lower alkoxypropylidene) dibenzo[a,d]cyclohepta[l,4,6]triene 10carboxylic acid di-(lower alkyl)amides and dibenzo[a,d]cyclohepta[1,4,6]trien-5-one 10 carboxylic acid cyclic amides, prepared,inter alia, from 5-(3-lower alkoxypropylidene)dibenzo[a,d]cyclohepta[l,4,6]triene 10- carboxylic acid, 10 halocarbonyl5-(3-lower alkoxypropylidene)dibenzo[a,d]cyclohepta[1,4,6]triene ordibenzo[a,d]cyclohepta[1,4,61trien-5 one IO-carboxylic acid halide, aredescribed. The end products are useful as antidepressants.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of US. Ser. No. 431,981, filed Feb. 11, 1965, nowabandoned.

BRIEF SUMMARY OF THE INVENTION The invention relates to compounds of theformula wherein R and R are each independently selected from the groupconsisting of hydrogen, halogen, lower alkyl, lower alkoxy; P and Q areeach independently selected from the group consisting of hydrogen, loweralkyl, benzyl, fi-picolyl, di-lower alkylamino, lower alkylaminoloweralkyl and amino-lower alky; P and Q, when taken together with the N atomare selected from the group consisting of piperidino, loweralkylpiperidino, piperazino, pyrrolidino, morpholino, N -hydroxy-loweralkylpiperazino and 4-(4" chlorobenzyDpiperazino; Z is selected from thegroup consisting of 0x0 and CH-A-B wherein A is lower alkylene and B isselected from the group consisting of halogen, lower alkoxy and loweralkylthio; and X is oxygen, sulfur or imido.

In another aspect, the invention relates to compounds of Formula Iwherein Z is oxo ketalized with lower alkanol, lower alkylenediol orlower alkylidene.

' 3,631,103 Patented Dec. 28, 1971 "ice wherein R and R' are eachindependently selected from the group consisting of hydrogen, halogen,lower alkyl and lower alkoxy; A is lower alkylene; B is selected fromthe group consisting of halogen, lower alkoxy, lower alkylthio; K isselected from the group consisting of bromine, chlorine, lower alkoxyand lower alkanoyloxy; P and Q are each independently selected from thegroup consisting of hydrogen, lower alkyl, benzyl, fi-picolyl, di-loweralkylamino, lower alkylamino-lower alkyl and amino-lower alkyl; P and Q,when taken together with the N atom are seected from the groupconsisting of piperidino, lower alkylpiperidino, piperazino,pyrrolidino, morpholino, N -hydroxy-lower alkyl-piperazino and4'-(4-chlorobenzyl)-piperazino; Z is selected from the group consistingof lower alkyl and --CH AB wherein A and B are as previously described;Z" is selected from the group consisting of bis (lower alkoxy), loweralkylenedioxy, lower alkylidene and CH-AB wherein A and B are aspreviously described; and T is lower alkylene.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates toantidepressant tricyclic compounds, intermediates useful in theirpreparation and methods for the preparation thereof. More particularly,the anti-depressant compounds of this invention are of the formula you,

I Z I wherein R and R are each independently selected from the groupconsisting of hydrogen, halogen, lower alkyl of l-4 carbon atoms, loweralkoxy of 1-4 carbon atoms; P and Q are each independently selected fromthe group consisting of hydrogen, lower alkyl of 1-4 carbon atoms,benzyl, ,B-picolyl, di-lower alkylamino of 1-4 carbon atoms, loweralkylamino-lower alkyl of 1-4 carbon atoms and amino-lower alkyl of 1-4carbon atoms; P and Q, when taken together with the N atom are selectedfrom the group consisting of piperidino, lower alkylpiperidino of l-4carbon atoms, piperazino, pyrrolidino, morpholino, N hydroxy-loweralkyl-piperazino of 1-4 carbon atoms and 4'-(4"-chlorobenzyl)piperazino;X is oxygen, sulfur or imido; and Z is selected from the groupconsisting of x0 and =CH-AB wherein A is an alkylene of 1-4 carbon atomsand B is selected from the group consisting of halogen, lower alkoxy of14 carbon atoms and lower alkylthio of 14 carbon atoms.

In another aspect, the invention relates to compounds of Formula Iwherein Z is oxo ketalized with lower alkanol, lower alkylenedioxy orlower alkylidene.

Preferred compounds of Formula I are those wherein R and R are hydrogenor halogen, P and Q are lower alkyl and when taken together with the Natom are morpholino; X is 0x0 and Z is 0x0 or =CHAB wherein A isethylene and B is lower alkoxy.

Most preferred compounds of Formula I are: -(3' methoxypropylidene)dibenzo[a,d]cyclohepta[1,4,61triene -carboxylic acid dimethylamide, andIO-(morpholinocarbonyl) 5H dibenzo[a,d]cyclohepta[l,4,6]trien- 5-one.

As indicated, the

in Formula I can represent either a free amino group or a mono ordi-substituted amino group. For example, it can represent a loweralkylamino group (especially the methyl, ethyl, propyl, isopropyl orbutylamino group) or an aralkylarnino group such as a phenyl-loweralkylamino group (especially benzylamino). Also, it represents a loweralkylamino group wherein the lower alkyl part is further substituted byan amino group (i.e., amino, lower alkylamino or di-lower alkylamino) ora heterocyclic moiety, e.g., pyridyl. Such substituted lower alkylaminogroups are, for example, dimethylaminoethylamino and pyridylmethylamino.Moreover, it can also represent a di-lower alkyl-amino group, the alkylmoieties of which each preferably contain l-4 carbon atoms (for example,the dimethylmino group, the diethylamino group or the methylethylaminogroup), a lower alkyl-aralkyl-amino group (for example, an N-loweralkyl-N-(phenyl-lower alkyl)- amino group such as the methyl-benzylaminogroup) or a di(aralkyl)a'mino group such as a di-(phenyl-lower alkyl)-amino group (for example, the dibenzyla-mino group). The lower alkylmoieties of these disubstituted amino groups can also be substituted byan amino group or a heterocyclic moiety, as indicated above with respectto the lower alkyl part of the lower alkylamino group. The

in Formula I, when P and Q are taken together, represents a substitutedor unsubstituted 5- or 6-membered heterocyclic moiety which is linkedthrough a nitrogen atom and may contain one other hetero atom. Examplesof such heterocyclic moieties are piperidino, piperazino, pyrrolidinoand morpholino, as well as the corresponding lower alkyl substitutedheterocyclic moieties, for example, methyl piperidino. Other substitutedheterocyclic moieties are also comprehended, for example N-hydroxy-loweralkyl-piperazino (for example, N-hydroxyethyl-piperazino).

The aromatic rings of the compounds of Formula I can be unsubstituted,i.e., where R and R are both hydrogen, or can be substituted. Thesubstituents represented by R and R are, for example, halogen(especially chlorine or bromine), lower alkyl of 1-4 carbon atoms(especially methyl or ethyl), lower alkoxy of l-4 carbon atoms(especially methoxy or ethoxy).

In the meaning of Z as =CHA-B, the symbol A, as indicated, represents analkylene residue of 1-4 carbon atoms. It preferably represents astraight chain or branched chain alkylene residue separating the moietydenoted by B from the pictured carbon atom by one or especiallypreferred, two carbon atoms. The symbol B denotes halogen (preferablychlorine or bromine), lower alkoxy of 1-4 carbon atoms (such as methoxyor ethoxy) or lower alkylthio of 14 carbon atoms (such as methylthio orethylthio). In its other meaning, Z can be oxo. It can also be ketalizedoxo wherein the ketalization is effected with either a lower alkyleneglycol, in which case Z represents a lower alkylenedioxy moiety; or witha lower alkanol, in which case Z represents, together with the5-position carbon atom, a moiety of the formula:

As indicated, there may be used as ketal-forming substances, loweralkanols and lower alkylene glycols, for example, methanol, ethanol orethylene glycol. In addition to the foregoing, Z can also represent alower alkylidene moiety, for example, methylidene or ethylidene.

The basic compounds of Formula I above form acid addition salts. Suchbasic compounds are, for example, those of Formula I wherein representsa basically substituted amino group. For example, the basic compounds ofFormula I form pharmaceutically acceptable acid addition salts with bothorganic and inorganic pharmaceutically acceptable acids such as, forexample, hydrobromic acid, hydrochloric acid, nitric acid, sulfuricacid, phosphoric acid, hydrochloric acid, nitric acid, sulfuric acid,phosphoric acid, acetic acid, formic acid, oxalic acid, succinic acid,citric acid, methanesulfonic acid, p-toluene sulfonic acid, and thelike. Acid addition salts of compounds of Formula I withpharmaceutically non-acceptable acids can be converted into free basessimply by neutralization, or can be converted into pharmaceuticallyacceptable acid addition salts by either neutralization followed byreaction with a pharmaceutically acceptable acid or by a simple exchangereaction with a pharmaceutically acceptable acid.

The compounds of Formula L above can be prepared from an acid of theformula:

wherein R, R and Z have the same meaning as above or a reactivefunctional derivative thereof, via reaction with ammonia or asubstituted amine, i.e. a compound of the formula:

III

P IIWN wherein l and Q have the same meaning as above.

In another embodiment, compounds of Formula I can be prepared fromcompounds of the formula:

INC P a HO Z V wherein R, R, P and Q have the same meaning as above, andZ is selected from the group consisting'of lower alkyl and -CH ABwherein A and B have the same meaning as above,

via dehydration to yield a compound of Formula 1.

i111 those compounds of Formula I obtained via the conversion of anintermediate of Formula III or Formula V wherein B represents halogen,the so-obtained halides can be further transformed within the definitiongiven for B, i.e. to ethers or thioet-hers. Moreover, the so-obtainedamides of Formula I (i.e.X=O) can be converted to t-hioamides (i.e. XS). Also, the so-obtained compounds of Formula I wherein Z is oxo can beketalized or reacted with a lower alkyl magnesium halide, theso-obtained organo-metallic compound hydrolyzed yielding a carbinol (forexample, of Formula V) which can then be dehydrated to yield a compoundof Formula I containing a semicyclic double bond in the 5-position. Inanother variant, compounds of Formula I wherein Z is a ketalized oxogroup can be hydrolyzed to yield corresponding compounds of Formula Iwherein Z is oxo.

The starting material compounds of Formula III can be prepared invarious ways, starting from ketone's of the formula:

Halogen wherein R and R have the same meaning as above.

Halogen C HA 0 lower alkyl VII wherein R and R have the same meaning asabove.

Several additional processes utilizing the ketone of Formula VI asstarting material are discussed hereinafter:

(a) A ketone of Formula V-I can be reacted with a propenyl halide bymeans of a metal-organic reaction. This reaction can be effected, forexample, by a lithium, zinc or, preferably, by a magnesiumorgano-metallic compound. The reaction product is then subjected tohydrolysis, preferably under conditions practically neutral, i.e.neither strongly basic nor strongly acidic, e.g. by treatment withammonium chloride. After the hydrolysis the elements of a hydrogenhalide can be added to the terminally unsaturated propenyl residue. Forexample, this reaction can be carried out in an advantageous manner bytreating the tricyclic reaction product bearing a terminally unsaturatedalkenyl residue with hydrogen bromide, conveniently with a solution ofhydrogen bromide in glacial acetic acid or chloroform at roomtemperature. The soobtained Sw-halo-propylidene derivatives are for themost part viscous, difiicultly crystallizable substances which can bedistilled undecomposed in a high vacuum. The exchange of the w-halogenatom for a lower alkoxy group can be effected, for example, viatreatment with an alkali metal alcoholate. An alkali metal compound of alower alkanol (e.g. sodium methylate or sodium ethylate) is especiallyadvantageous for this purpose. The exchange reaction is convenientlyetfected at the boil in the presence of an excess of the alkanolcorresponding to the alcoholate used.

(b) A ketone of Formula VI can be reacted with a cyclopropyl halide bymeans of a metal organic reaction and the reaction product can then betreated with a halogenating agent according to the conditions mentionedin process variant (a) above to yield theomega-halopropylidene-substituted compounds which can then be furtherreacted as described under (a).

(c) A ketone of Formula VI can be reacted directly with a loweralkoxypropyl halide. This reaction is preferably carried out via amagnesium compound according to the conditions given under (a) above.Examples of such lower alkoxypropyl halides are, for example, 1-chloro-2-methyl-3-methoxypropane, l-chloro-3-rnethoxypropane, and thelike. The lower alkoxy group is advantageously one such as methoxy,ethoxy, propoxy, butoxy or the like and is advantageously at the endposition (omega position) of the alkyl halide. Thus, w-rnethOXY- propylmagnesium compounds are preferred starting materials. Resides loweralkoxy, the ether function can also be, for example, ar-alkoxy (forexample, phenyl-lower alkoxy such as benzyloxy or phenethyloxy) or alsotetrahydropyranyloxy. The reaction products are hydrolyzed as describedunder (a) above and can then be subsequently dehydrated. According to amodification of the procedure, there can be used as a starting materiala ketone of Formula VI containing no halogen substituent in thel0-position. After the introduction of the alkoxypropylidene residue inthe 5-position, a halide substituent can then be introduced into thel0-position by treatment with a halogenating agent and subsequentsplitting out of the elements of hydrogen halide. For the introductionof this halogen substituent, the S-alkoxypropylidene derivative isconveniently treated in an inert solvent such as a halogenatedhydrocarbon (e.g. carbon tetrachloride) with a halogen (e.g. chlorine orbromine). This treatment with halogen is preferably carried out in thepresence of a catalyst. This halogenation yields 10,11-dihalo compoundswhich can be converted into ether derivatives of Formula VII via thesplitting out of the elements of hydrogen halide. The splitting out canbe effected, for example, by means of an alkali carbonate or alkalihydroxide.

(d) A ketone of Formula VI can be reacted with an alkali metal compoundof the formula:

M--CECCHgO-1OWI' alkyl wherein M is an alkali metal.

(VIII) The so-obtained compound can then be hydrolyzed to yield acompound of the formula:

Halogen H O C E 0 0 H O-lower alkyl (IX) absolute ether, benzene ortetrahydrofuran, to the alkali metal organic compound of Formula VIII,the latter being suspended in liquid ammonia. The decomposition of theresultant metal organic compound is advantageously effected underpractically neutral conditions (e.g. ammonium chloride or an aqueousammonium chloride solution). The products so-obtained are subsequentlysaturated (hydrogenated) at the side chain triple bond and thendehydrated. The hydrogenation is conveniently effected in the presenceof a noble metal catalyst (e.g. platinum oxide) under normal conditions.After the theoretical amount of hydrogen to saturate the triple bond hasbeen absorbed, the hydrogenation is advantageously immediately stopped.

(e) A tricyclic ketone of Formula VI can be reacted with a lower alkylmagnesium halide. The carbinol, i.e. the 5-hydroxy-5-alkyl derivative,formed after hydrolysis of the metal-organic reaction product, can thenbe converted by dehydration into the corresponding 5-lower alkylidenecompound with a semicyclic double bond. The so-obtained intermediatescontaining the 5 lower alkylidene substituent, can then be convertedinto IO-carboxy compounds or, alternatively, can be treated with ahalogenating agent, for example a compound containing a S-ethylidenesubstituent can be halogenated to a corresponding compound containing aB-haloethylidene substituent. The B-haloethylidene moiety can, in turn,be converted into a fi-lower alkoxy ethylidene moiety according to theconditions given under (a).

(f) A ketone of Formula VI can be converted into a correspondingcompound containing a ketalized oxo group in the 5-position viaconventional ketalization means, i.e. by treatment with a lower alkyleneglycol such as ethylene glycol or by treatment with a lower alkanol suchas methanol or ethanol.

Compounds of Formula III containing a IO-carboxy group can be obtainedfrom the corresponding 10-halo compounds obtained as described above(e.g. in process variants (a)-(f)) by exchange of the halogen atom inthe IO-position for a carboxy group which may be functionally modified.

Compounds of Formula III can thus be obtained from corresponding IO-halocompounds via several different methods. In one method, thecorresponding 10-halo compound can be treated in an inert solvent (e.g.tetrahydrofuran) with magnesium and the so-obtained magnesiumorganiccompound reacted with carbonic acid. Hydrolysis then yields alO-carboxylic acid of Formula III which, if desired, can be converted ina manner known per se into its functional derivatives such as esters(especially with lower alkanols), carbonyl halides (especially chloridesand bromides), or anhydrides. To obtain compounds of Formula III whereinZ is 0x0, it is suitable to protect the 5-oxo group of the lO-halostarting material prior to the treatment with magnesium. This protectionis suitably effected via ketalization, for example, with ethyleneglycol. After the treatment with carbonic acid, the ketal group can behydrolyzed to regenerate the 5-oxo group or alternatively the ketalgroup can be regenerated after subsequent reaction steps.

Compounds of Formula III can also be obtained from corresponding lO-halocompounds via treatment of the latter with a metal cyanide (e.g. sodiumcyanide, potassium cyanide or copper cyanide) in an inert solventwhereby there is obtained a compound corresponding to those of FormulaIII which, instead of the lO-carboxy group pictured in Formula III,carries a lO-cyano substituent. Via saponification of the cyano group,the desired lO-carb0xy compound of Formula III can be obtained.Functional derivatives of the 10-carboxy substituent can be preparedaccording to known methods as indicated above. Prior to the treatmentwith the metal cyanide, it is suitable to protect a 5-oxo group viaketalization, if the starting material used contains such.

Starting materials of Formula MI in which Z is =CH-AB and B is halogen,can be prepared, for example, from the corresponding alkoxy substitutedcompounds, by treatment with hydrogen halide or especially by treatmentwith boron trihalide. In one convenient method, the alkoxy substitutedalkylidene compound of Formula III is treated with a 2-molar quantity ofboron trihalide in the presence of an inert solvent, e.g. methylenechloride, at a low temperature, for example, at about l0 C.

Starting materials of Formula V which, as indicated above, can beconverted via dehydration to the desired end products of Formula I, canthemselves be obtained from the ketones of Formula VI. Thus, the halosubstituent in the IO-position of the ketone of Formula VI can bereplaced by the cyano group by treatment with a metal cyanide(especially preferred is a copper cyanide). After saponification of thecyano group and reaction of the so-formed free carboxylic acid or one ofits functional derivatives with an amine, there are obtained compoundsof Formula I wherein Z is oxo, i.e. 10 carbamoyldibenzo[a,d]cyclohepta[1,4,6]trien-5- ones. These latter 5-oxo compoundscan be converted into compounds of Formula V; for example, via reactionwith an alkali metal compound of Formula VIII, Subsequent hydrolysis andhydrogenation according to the conditions mentioned under ((1).

The manifold possibilities for the production of the starting materialsdiscussed in the foregoing paragraphs are only exemplary. Numerous otherprocess variants are available and will be apparent to those skilled inthe art.

The compounds of Formula III can be reacted directly with ammonia or thesubstituted amines of Formula IV in the form of the free acid oralternatively, as a functional derivative. When the free acid of FormulaIII is used, the reaction is conveniently carried out in the presence ofa condensing agent, e.g. an N,N-disubstituted carbodiimide. Reactiveacid derivatives which can be used are, for example, lower alkyl esters,carbonyl halides (especially chlorides or bromides), nitriles andanhydrides of the IO-carboxy acids of Formula III. When nitriles areused, amidine derivatives are obtained (for example by treatment of thenitrile With an amine magnesium halide in an inert organic solvent suchas ether or tetrahydrofuran, a guanyl (X-imido) compound of Formula I isobtained. It should be noted that, if a nitrile starting materialcontaining an 0x0 group is used, the S-oxo group should be protected byketalization prior to the treatment with the amine-magnesium halide. Forreaction with the free acid of Formula III or the lower alkyl ester,carbonyl halide or anhydride functional derivatives thereof, there issuitably used a compound of Formula IV, for example, ammonia, a loweralkyl amine (e.g. methylamine), a dilower alkyl amine (e.g.dimethylamine) or a heterocyclic amine such as piperidine, morpholine,N-hydroxyethylpiperazine, or the like. Especially preferred are thedilower alkylamines, such as dimethylamine.

When the reaction is effected with a carbonyl chloride corresponding toFormula III (which acid chlorides are accessible from the free acids ofFormula III, for example, by treatment of the latter with thionylchloride with heating), the amidation is conveniently effected at a verylow temperature, for example from about 0 C. to about 30 C. Esters whichcan be obtained from the free acids in a manner known per se areadvantageously reacted with the desired amine at an elevatedtemperature, under elevated pressure if necessary.

Compounds of Formula V can be dehydrated as indicated above. Thisdehydration is advantageously effected by heating the compound ofFormula V with a lower alkanolic hydrochloric acid. However, it is alsopossible to dehydrate with other dehydration agents such as, forexample, phosphorous oxychloride, p-toluene-sulfonyl chloride, sulfuricacid, zinc chloride, potassium bisulfate,

or the like, in an inert organic solvent (such as, for example,chloroform or methylene chloride).

As indicated above, in those products of Formula I obtained viaamidation or dehydration wherein the symbol Z is =CI-I-AB, thesubstituent represented by B can itself be further transformed inreaction steps subsequent to the amidation or dehydration. For example,compounds of Formula I in which said substituent B represents a halogenatom can be reacted with a metal alcoholate or metal alcoholate or metalmercaptan, preferably an alkali metal lower alcoholate or an alkalimetal lower alkyl mercaptan, conveniently in the presence of the loweralcohol corresponding to the alcoholate or mercaptan used. Suitably, themetal compound is added suspended in an inert solvent. Compounds ofFormula I wherein B is lower alkoxy or lower alkylthio are thusobtained.

Moreover, carboxylic acid amides of Formula I can be converted tocorresponding thioamides of Formula I by treatment withphosphorus-sulphur compounds (e.g. phosphorus pentasulfide), preferablyin a neutral, anhydrous solvent or diluent at a temperature from about50 C. to about 120C.

Compounds of Formula I wherein Z represents a ketal group can beconverted to corresponding ketones, i.e. wherein Z is oxo, via warmingwith dilute acids (for example, dilute mineral acids). The oxo group inketones of Formula I can themselves be transformed into lower alkylidenemoieties, for example by reaction of the ketone with an alkyl magnesiumhalide. This latter conversion is only possible if the amino group andthe imido group X are resistant to the Grignard reagent used.

The compounds of Formula I can occur in various isomeric forms. Mixturesof different isomers can be separated into the separate cis and transantipodes according to methods known per se; for example, by fractionalcrystallization on the basis of different solubility of the individualisomers or derivatives thereof. Separation of the geometrical isomerscan be effected with the starting materials or at the intermediatestages. Subsequent reaction then yields pure isomers and, in thisinstance, the end products of Formula I are obtained in the form of apure geometric isomer.

The compounds of Formula I, as well as their pharmaceutically acceptableacid addition salts are characterized by their antidepressant action onthe central nervous system and are useful as antidepressants. They areespecially useful as antidepressants in that they give rise to only avery slight anti-cholinergic effect. These compounds are useful not onlyin relief of symptomatology associated with depression of the centralnervous system, but are also useful in the prevention and reversal ofcentral nervous system depression caused by exogenous chemical agents.An especially advantageous subclass of compounds of Formula I are thosewherein R and R are both hydrogen.

The compounds of Formula I as well as their pharmaceutically acceptableacid addition salts, can be administered internally for example,enterally (e.g. orally) or parenterally, with dosage adjusted toindividual requirements. They can be administered in the form ofconventional pharmaceutical preparations containing conventional organicor inorganic pharmaceutical solid or liquid carried materials suitablefor enteral, e.g. oral, or par enteral administration. For example, thepharmaceutically active ingredient of Formula I or a pharmaceuticallyacceptable acid addition salt thereof can be compounded according toconventional methods with conventional pharmaceutical carriers which donot react with the active ingredient, such as Water, gelatin, lactose,starches, magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols, petroleum jelly and the like. The pharmaceutical preparationscan be in solid form, for example, tablets, drages, suppositories orcapsules, or in liquid form, for example, solution, emulsions orsuspensions. If desired, they can be submitted to pharmaceuticalexpedients such as sterilization or can contain conventional excipientssuch as preservatives, stabilizing agents, wetting or emulsifyingagents, salts for the adjustment of osmotic pressure, or buffers, andthey also can contain, in combination, other therapeutically activesubstances.

I The useful psychopharmacological antidepressant activrty of thecompounds of Formula I is demonstrated in warm-blooded animals utilizingstandard procedures. For example, groups comprising 1-0 mice each areadministered the test substance in variable amounts subcutaneously.After 16 hours, they are given subcutaneously 5 mg./kg. of 2hydroxy-Z-ethyl-3-isobutyl-9,lO-dimethoxy 1,2,3,4,6,7-hexahydro-llbH-benzyl[a]quinolizine (substance A), and 30 minutesthereafter, they are given intraperitoneally mg./kg. of ethanol. Acontrol group of 10 animals 1s given only ethanol. The duration of sleepis measured in all animals. The percentage decrease in duration in sleep1n comparison with the duration of the substance A potentlated sleepreflects the psychopharmacological antidepressant elfect.

When 5-(3' methoxy-propylidene)dibenzo[a,d] cyclohepta[1,4,6]trienel-carboxylic acid dimethylamide, Wl'llCh has an LD of 2000 mg./ kg.p.o., is utilized as the test substance at a dosage of 20 mg./kg. s.c.,a correspondmg 54 percent decrease in duration of sleep is produced, andat a dosage of 10 mg./ kg. s.c., a corresponding 45 percent decrease induration of sleep is produced.

When l0-morpholinocarbonyl-dibenzo [a,d] cyclohepta- [1,4,6]trien--one,whcih has an LD of 350 mg./ kg. pm. is utilized as the test substance ata dosage of 20 rug/kg: s.c., a corresponding 56 percent decrease induration of sleep is produced.

The following examples are illustrative but not limitative of theinvention. All temperatures are stated in degrees centigrade.

Example 1 A solution of 16.2 g. of 5-(3'-methoxy-propylidene) d1benzo[a,d]cyclohepta[ l,4,6]triene IO-carboxylic acid chloride in 50 ml. ofdry benzene is added dropwise with stirring to a solution of g. ofdimethyl amine in 100 ml. of dry benzene. During the addition, thetemperature is held at -25 with a cold water-bath. After the additron,the reaction mixture is stirred for a further minutes at 20, boiledunder reflux conditions for 30 minutes, and then the benzene and theexcess amine are distilled off under reduced pressure. The residue istaken up in benzene, the solution washed with water; dilute hydrochloricacid, water, sodium bicarbonate solution and again with water, dried andevaporated. Recrystallization of the residue from high-boiling petroleumether, yields 5- (3-methoxypropylidene) dibenzo[a,d]cyclohepta[1,4,6]triene 10-carboxylic acid dimethyl amide which melts at Ill-112.

The 5 (3-methoxy-propylidene)-dibenzo[a,d]cyclohepta[1,4,6]trieneIO-carboxylic acid used as the starting compound is manufactured asfollows:

In a 2-liter round flask which is provided with stirrer, dropping funneland reflux condenser, 15 g. of magnesium shavings are covered with 20ml. of dry ether, and then treated with 0.5 ml. of methyl iodide. Assoon as the reaction has started, a solution of 54.6 g. of l-methoxy-3-chloro-propane in 300 ml. of ether is added dropwise in such a waythat the reaction mixture is held at boiling. After the dropwiseaddition is completed, the reaction mixture is boiled under reflux for afurther 3 hours.

The reaction mixture is then cooled with ice-water, a solution of 69.2g. of IO-bromo-dibenzo[a,d]cyclohepta- [1,4,6]triene-5-one in 500 ml. ofether is added dropwise in the course of minutes, and the whole reactionmixture is then stirred under reflux at for 16 hours.

On the following day the reaction mixture is once again cooled withice-water and is treated with a cold saturated ammonium chloridesolution. The organic layer is then separated, the aqueous phase shakenup with 200 ml. of ether and the combined ether portions dried oversodium sulfate and evaporated. After recrystallization from high-boilingpetroleum ether, the residue yields colorless crystals of S-hydroxy 5(3'-methoxypropyl)-10- bromo-dibenzo[a,d]-cyclohepta[1,4,6]trienemelting at 8284.

50 g. ofS-hydroxy-S-(3-methoxy-propyl)-10-bromo-dibenzo[a,d]-cyclohepta[l,4,6]trieneand 500 ml. of 3 percent alcoholic hydrochloric acid solution are heatedunder reflux conditions on the steam-bath for 3 hours, and the solutionevaporated under reduced pressure. The residue is then taken up in 300ml. of ether, the ethereal solution is washed with aqueous sodiumbicarbonate, thereafter washed with water, dried over sodium sulphateand evaporated. After distillation of the residue under 0.055 mm. Hg at155 and repeated recrystallization from petroleum ether, colorlesscrystals of 5-(3-methoxy-propylidene)-10-bromo-dibenzo[a,d]cyclohepta[1,4,61triene melting at 113-115 areobtained.

In a 1 liter three-necked flask provided with stirrer, dropping funneland reflux condenser, 6 g. of magnesium shavings are treated with a fewdrops of methyl iodide and, as soon as the reaction has started, asolution of 68 g. of 5-(3-methoxy-propylidene)-10-bromo-dibenzo-[a,d]cyclohepta[l,4,6]triene in 300 ml. of dry, peroxidefreetetrahydrofuran is added dropwise in such a way that the internaltemperature is maintained between 50 and 55. Subsequently, the reactionmixture is boiled under reflux for a further 3 hours, during whichrefluxing, the magnesium almost completely disappears.

The resultant light brown solution is cooled at 20, and is then treatedwith a dry stream of carbonic acid. After 2 hours the reaction hasended, and the reaction mixture is decomposed with a saturated ammoniumchloride solution. The tetrahydrofuran is then evaporated off underreduced pressure, the residue extracted with ether and the etherealsolution extracted with dilute sodium carbonate solution. The reactionproduct precipitates out on acidification of the alkalie solution withhydrochloric acid. It is then extracted with ether, the etherealsolution. washed, dried and evaporated. After recrystallization fromacetic ester/ petroleum ether, 5-(3'-methoxy-propylidene)-dibenzo[a,d]cyclohepta[1,4,6] 10 carboxylic acid is obtained in the formof colorless crystals melting at 177 15.3 g. of5-(3-methoxy-propylidene)-dibenzo[a,d]cyclohepta-[1,4,6]triene10-carboxylic acid and 50 ml. of thionyl chloride are boiled underreflux conditions for 3 hours. The excess thionyl chloride is distilledunder reduced pressure and the residue is recrystallized from petroleumether. The so-obtained5-(3-methoxy-propylidene)-dibenzo[a,d]cyclohepta[1,4,61trieneIO-carboxylic acid chloride melts at 106108.

Example 2 16.2 g. of5-(3'-methoxy-propylidene)-dibenzo[a,d]cyclohepta[1,4,6]triene10-carboxylic acid chloride is dissolved in 70 ml. of dry benzene andadded dropwise at 2025 to a mixture of 12.2 g. of methyl-(fl-picolyD-amine and 100 ml. of dry benzene. The reaction mixture is then furtherstirred for an additional hour at 20, diluted with ether and extractedwith dilute hydrochloric acid. The acidic solution is treated withexcess potassium carbonate, and the precipitated oil extracted withether, the ether phase dried and evaporated, yielding 5-(3'- methoxypropylidene) dibenzo[a,d]cyclohepta[1,4,6] triene 10-carboxylic acidN-methyl-N-(,Bpicolyl)amide. The hydrochloride of this substance isformed and recrystallized from ehanol/ether and melts at 103105.

l 2 Example 3 By the replacement of the methyl-(fl-picolyD-amine inExample 2 with 26 g. of 4-hydroxyethyl-piperazine there is obtained (3methoxypropylidene)--[4-(2-hydroxy-ethyl)-piperazino carbonyl]dibenzo[a,d]cyclohepta[1,4,6]triene, the hydrochloride of which(recrystallized from ethanol/ether) melts at 210-213.

Example 4 By the replacement of the methyl-(fi-picolyD-amine in Example2 with 10 g. of dimethylamino-ethylamine there is obtained5-(3-methoxy-propylidene)-dibenzo[a,d]cyclohepta[1,4,6]triene10-carboxylic acid 2-dimethylamino-ethylamide as colorless crystals(melting at 118- 119).

Example 5 A solution of 4.0 g. of dimethylamine in 100 ml. of ether isadded dropwise at room temperature to a solution of ethyl magnesiumbromide (prepared from 1.9 g. of magnesium shavings, 8.2 g. of ethylbromide and 100 ml. of ether). The reaction mixture is then heated for20 minutes under reflux, cooled to 20 and treated with a solution of14.35 g. of 5-(3'-methoxy-propylidene)-dibenzo[a,d]-cyclohepta[l,4,6]triene l0-carboxylic acid nitrile in 100 ml. of ether.The whole reaction mixture is then boiled for 3 hours under refluxconditions, cooled with ice-water and decomposed with a cold saturatedammonium chloride solution. There precipitates a mixture of hydrobromideand hydrochloride which is filtered off by suction, and is shaken forhours with 10 g. of freshly precipitated silver chloride in 800 ml. ofwater in the absence of light. Filtration, evaporation andrecrystallization of the residue from methanol/ether yields 5-(3-methoxy-propylidene) dibenzo[a,d] cyclohepta[1,4,6] triene 10-carboxylicacid N,N-dimethyl amidine hydrochloride in the form of colorlesscrystals melting at 290291.

The 5-(3'-methoxy propylidene)dibenzo[a,d] cyclohepta[1,4,6]trieneIO-carboxylic acid nitrile used as starting material can be manufacturedas follows:

17.05 g. of5-(3'-methoxy-propylidene)-10-bromo-dibenzo[a,d]-cyclohepta[1,4,6]triene,9.0 g. of cuprous cyanide and 50 ml. of dimetholformamide are heatedunder reflux conditions for 5 hours with stirring. The dimethylformamideis then distilled off under reduced pressure and the residue isextracted with boiling benzene. After evaporation of the benzene thereremains behind an oil which boils at 170 under 0.005 mm. Hg. The oil isrecrystallized from high boiling petroleum ether yielding 5 (3 methoxypropylidene) dibenzo[a,d]cylohepta [1,4,6]triene carboxylic acid nitrilewhich melts at 92-94".

Example 6 16.2 g. of 5-(3-methoxy-propylidene)-dibenzo[a,d]cyclohepta[1,4,6]triene 10-carboxylic acid chloride is dissolved in 50ml. of dry benzene and the resultant solution is then added dropwisewith stirring at to a solution of 12.1 g. of methyl-benzylamine in 100ml. of dry benzene. The reaction mixture is stirred for a furtherminutes at 20, then 30 minutes at diluted with ether, washed, dried andevaporated. By recrystallization of the residue from methanol/ water5-(3'-methoxy-propylidene) dibenzo[a,d]cyclohepta[1,4,6]-triene10-carboxylic acid N-methyl-N-benzyl amide (melting at 124126) isobtained.

Example 7 By reaction of 5-(3'-methoxy-pr0pylidene)-dibenzo[a,d]-cyclohepta[1,4,6]triene IO-carboxylic acid chloride with diethylamine in benzene there is obtained 5-(3- methoxy propylidene)dibenzo[a,d]cyclohepta[1,4,6] triene IO-carboxylic acid diethyl amidewhich is recrystallized from benzene/petroleum ether and melts atl18-120.

1 3 Example 8 10 g. of-(3-methoxy-propylidene)-dibenzo[a,d]cyclohepta[1,4,6]trieneIO-carboxylic acid dimethyl amide, 6.66 g. of phosphorus pentasulphideand 100 ml. of dry benzene are heated under reflux conditions for 2hours, and the reaction mixture then filtered While still warm. Thesolid residue is extracted twice, each time with 150 ml. of boilingbenzene, and the combined benzene extracts are evaporated to dryness.There remains behind g. of 5-(3'-methoxy propylidene) dibenzo[a,d]cyclohepta [1,4,6]triene 10-carboxylic acid thiodimethyl amide which,after recrystallization from benzene/petroleum ether, melts at l84-l85.

Example 9 20 g. of 5- 3 -methoxy-propylidene -dibenzo [a,dcyclohepta[l,4,6]triene lO-carboxylic acid is dissolved in 80 ml. ofmethylene chloride and treated dropwise at 1O with a solution of 16 g.of boron trichloride in 40 ml. of methylene chloride. After the dropwiseaddition, the reaction mixture is stirred for a further hours at Thesolution obtained is then completely evaporated under reduced pressure,the residue dissolved in dry benzene, again evaporated, the newlyobtained residue dissolved in 100 ml. of dry benzene and this solutionslowly added to a mixture of 30 g. of dimethyl amine and 300 ml. of drybenzene. The reaction mixture is now further stirred at 20 for 30minutes, then washed with water, dilute hydrochloric acid, water, sodiumcarbonate solution and lastly with water, dried and evaporated. Byrecrystallization of the residue from high boiling petroleum ether 5(3'-chloropropylidene) dibenzo [a,d] cyclohepta[ 1,4,6] trieneIO-carboxylic acid dimethyl amide of melting point 141-143" is obtained.

Example 10 6 g. of5-(3'-ethoxy-propy1idene)-dibenzo[a,d]cyclohepta[1,4,6]triene10-carboxylic acid and ml. of thionyl chloride are heated for 3 hoursunder reflux conditions. The excess thionyl chloride is then distilledoff under reduced pressure, the residue dissolved in 50 ml. of drybenzene and this solution added dropwise at 20-30 to a mixture of 10 g.of dimethylamine and 100 ml. of dry benzene. The whole reaction mixtureis then heated for a further minutes under reflux conditions, cooled,washed with dilute hydrochloric acid, water, sodium carbonate solutionand water, dried and evaporated. After recrystallization from highboiling petroleum ether the residue yields colorless crystals of5-(3-ethoxy-propylidene) dibenzo[a,d]cyclohepta[1,4,6]trienel0-carboxylic acid dimethyl amide melting at l23l24.

The 5-(3-ethoxy-propylidene) dibenzo[a,d] cyclohepta[l,4,6]triene10-carboxylic acid used as starting material can be manufactured asfollows:

30 g. of magnesium shavings (in a round flask which is fitted with astirrer, dropping funnel and reflux condenser) are treated with asolution of 123.5 g. of l-chloro- 3-ethoxypropane in 600 ml. of dryether in such a way that the ether is kept slightly boiling. Thereaction mixture is then heated with stirring under reflux conditionsfor a further 3 hours, after which it is cooled with icewater, and asolution of 138.4 g. of l0-bromo-dibenzo[a,d]cyclohepta[1,4,6]triene-5-one in 800 ml. of dry ether is addeddropwise in the course of 60 minutes. After the addition is completed,the whole reaction mixture is stirred at for 15 hours.

On the following day the reaction mixture is once more cooled with ice,and then treated with a cold saturated ammonium chloride solution. Theorganic layer is separated, the aqueous phase twice extracted, each timewith 200 ml. of ether, and the combined ether-portions dried over sodiumsulphate and evaporated. After recrystallization from petroleum etherthe residue yields S-hydroxy-S- (3-ethoxypropyl) l0bromo-dibenzo[a,d]cyclohepta [1,4,6]triene melting at 68-72.

50 g. of5-hydroxy-5-(3-ethoxy-propyl)-l0-bromo-dibenzo[a,d]cyclohepta[1,4,6]trieneand 500 ml. of a 3 percent alcoholic hydrochloric acid solution areboiled under reflux for 3 hours and the resultant solution evaporatedunder reduced pressure. The residue is taken up in 300 ml. of ether, theso-obtained ethereal solution washed with aqueous sodium carbonate,dried over sodium sulphate and evaporated. 5-(3'-ethoxy-propylidene) 10bromodibenzo[a,d]cyclohepta[1,4,61triene melting at 92-95 is obtained byrecrystallization of the residue from high boiling petroleum ether.

1.8 g. of magnesium shavings (in a round flask fitted with stirrer,dropping funnel and reflux condenser) are treated with single drops ofmethyl iodide and as soon as the reaction has started a solution of 20g. of 5-(3- ethoxy-propylidene) 10 bromo-dibenzo[a,d]cyclohepta[1,4,6]triene (melting at 9295) in ml. of dry, peroxide-freetetrahydrofuran is added dropwise in such a way that the internaltemperature is held between 50 and 60. Subsequently, the reactionmixture is boiled under reflux for a further 3 hours, whereby themagnesium almost completely disappears.

Dry carbonic acid is then passed for 2 hours into the resultant brownsolution which is cooled to 20. Then the reaction mixture is decomposedwith a cold saturated ammonium chloride solution, the tetrahydrofurandistilled off under reduced pressure, the residue extracted with etherand the ethereal solution extracted with dilute sodium carbonatesolution. The reaction product precipitates on acidification of thisalkaline solution with hydrochloric acid and is taken up in ether. Theethereal solution is then washed, dried and evaporated. Afterrecrystallization from ethyl acetate/petroleum ether the 5-(3' ethoxypropylidene) dibenzo [a,d]cyclohepta[1,4,6]triene 10-carboxylic acidforms colorless crystals melting at l15.

Example 11 5 g. of5-(3-methoxy-propylidene)-dibenzo[a,d]cyclohepta[l,4,6]trienel0-carboxylic acid methyl ester and 20 ml. of a methanolic ammoniasolution are heated at 100 for 3 hours in a sealed tube. Afterevaporation off the methanol there remains behind the5-(3'-methoxy-propylidene)-dibenzo[a,d]cyclohepta[l,4,6]triene10-carboxylic acid amide which is recrystallized from benzene/petroleumether and melts at 164166.

The 5-(3-n1ethoxy propylidene) dibenzo[a,d]cyclohepta[1,4,6]triene10-carboxylic acid methyl ester used as starting material can bemanufactured as follows:

16 g. of 5 (3'-methoxy-propylidene)dibenzo[a,d]- cyclohepta[1,4,6]trienelO-carboxylic acid chloride is dissolved in 30 ml. of dry acetone, addeddropwise with stirring to 200 ml. of methanol and the whole reactionmixture boiled for about 10 minutes. The alcohol is then evaporated, theresidue taken up in ether, the ethereal solution washed with sodiumcarbonate, dried and evaporated. The 5-(3'methoxy-propylidene)-dibenzo[a,d] cyclohepta[l,4,6]triene IO-carboxylicacid methyl ester is recrystallized from petroleum ether and melts at87-88.

Example 12 By replacement of the ammonia in Example 11 withmonomethylamine there is obtained 5 (3-methoxypropylidene)dibenzo[a,d]cyclohepta[1,4,6]triene 10- carboxylic acid methyl amide ofmelting point l78l80 (recrystallized from benzene/petroleum ether).

Example 13 By reaction of 5 (3-methoxy-propylidene)-dibenzo[a,d]cyclohepta[1,4,6]triene IO-carboxylic acid chloride with4-chlorobenzyl-piperidine in benzene there is obtained 5 (3'methoxypropylidene)-10-[4'-(4"-chlorobenzyl)- piperazino carbonyl]dibenzo[a,d]cyclohepta[1,4,6] triene, which is recrystallized frommethanol/ water and melts at 163-164".

25 g. of polyvinylpyrrolidone is dissolved in 120 g. of isopropanol inan appropriate vessel (e.g. wide neck flask). To this mixture there isadded portionwise, while stirring, a mixture of 100 g. of-(3-methoxy-propylidene)- dibenzo[a,d]cyclohepta[l,4,6]triene carboxylicacid dimethyl amide, 500 g. of lactose and 300 g. of corn starch. Themoist mass is granulated through a suitable sieve and dried at about 60in an aerated drying oven.

To the dried granulate are added 25 g. of corn starch, 40 g. of talc and10 g. of magnesium stearate, whereupon the mixture is thoroughly mixedand pressed into kernels, the weight of which depends upon the dosage ofactive substance (for example, 112 mg. for 10 mg. drages; 280 mg. for 25mg. drages).

After drying, the kernels are covered (up to 60 percent of their weight)with a layer of concentrated sugar syrup containing 5 percent each ofstarch and talc, and dried several hours at aboutt 35.

Drageification is then continued with a concentrated sugar syrup untilthe weight of the layer equals that of the kernel. The drages arefinally polished with one or more appropriate waxes and dried severalhours.

Example A solution of 12.6 g. of 10-chlorocarbonyl-dibenzo[a,d]cyclohepta[l,4,6]trien-5-one in 50 ml. of dry benzene is added dropwisewith stirring to a solution of 10 g. of dimethylamine in 100 ml. of drybenzene. During the addition, the temperature of the reaction mixture ismaintained at 25 via external cooling. After the addition, the reactionmixture is stirred minutes and is then heated under reflux for still afurther 30 minutes. The benzene and excess dimethylamine is thendistilled off under reduced pressure. The residue is taken up in benzeneand the resultant solution washed with water, dilute hydrochloric acid,water, sodium bicarbonate solution and then once again with water. Thesolution is then dried and concentrated yielding as the residue,dibenzo[a,d] cyclohepta[l,4,6]trien-5-one 10-carboxylic aciddimethylamide which, after recrystallization from high boiling petroleumether, melts at 146-147.

The 10-chlorocarbonyl-dibenzo[a,d]cyclohepta[1,4,6] trien-S-one used asthe starting compound can be prepared as follows:

In a 500 ml. round bottom flask equipped with a stirrer, refluxcondenser and gas inlet tube, g. oflO-bromodibenzo[a,d]cyclohepta[1,4,6]trien-5-one is dissolved in 150 ml.of ethylene glycol. The solution is then saturated with hydrogenchloride gas. During the addition of the gas, the solution is stronglyagitated and the temperature rises to After the addition, the reactionmixture is stirred for. one hour at (bath temperature), then cooled andpoured into excess ice cold caustic soda. The reaction mixture is thenfiltered with suction and recrystallized from high boiling petroleumether to yield 10 bromo 5,5 ethylenedioxy-dibenzo[a,d]cyclohepta[1,4,6]triene melting at 171172.

In a one liter 3-necked flask, equipped with a stirrer, a droppingfunnel and a reflux condenser, a few drops of methyl iodide are added to9 g. of magnesium shavings. As soon as the reaction has started, asolution of 78.6 g. of 10 bromo-5,5-ethylenedioxy-dibenzo[a,d]cyclohepta[1,4,6]triene in 450 ml. of dry, peroxide-free tetrahydrofuran is addeddropwise in such a manner that the reaction mixture is maintained at atemperature between 40 and 42. After the addition is completed, thereaction mixture is heated for a further 3 hours under reflux conditionsand during this heating the magnesium nearly completely disappears.After the heating, a stream of dry carbon dioxide gas is introduced at-40 into the resultant yellow brown solution. After two hours, thereaction terminates. The reaction mixture is then decomposed via theaddition of a saturated ammonium chloride solution. The tetrahydrofuranis then evaporated off under 1 6 reduced pressure and the residuedissolved with methylene chloride and the resultant solution extractedwith dilute sodium carbonate solution. The alkaline solution is thenesterified with hydrochloric acid yielding, as a precipitate, 10 carboxy5,5 ethylenedioxy-dibenzo [a,d]cyclohepta[1,4,6]triene which, afterrecrystallization from ethyl acetate/petroleum ether, melts at 276278.

50 g. of 10-carboxy-S,S-ethylenedioxy-dibenzo[a,d]cyclohepta[l,4,6]triene, 50 ml. of concentrated hydrochloric acid and 500 ml. ofacetone are heated together for one hour under reflux conditions. Thesolvents are then evaporated otf and the residue dissolved in aqueoussodium bicarbonate. The so-obtained solution is then filtered overcharcoal and esterified with hydrochloric acid. The precipitatedreaction product is then taken up in methylene chloride solution, driedand concentrated. The so-obtained residual10-carboxy-dibenzo[a,d]cyclohepta[l,4,6]trien 5- one, afterrecrystallization from ethyl acetate/ petroleum ether, melts at 202204.

12.5 g. of 10-carboxy-dibenzo[a,d]cyclohepta[l,4,6]trien-S-one and 40ml. of thionyl chloride are heated together for one hour under refluxconditions. The excess thionyl chloride is then distilled off underreduced pressure, yield ing as the residue, crude solid10-chlorocarbonyl-dibenzo- [a,d]cyclohepta[1,4,6]trien-5-one.

Example 16 10 g. of lO-chlorocarbonyl-dibenzo[a,d]cyclohepta-[1,4,6]trien-5-one is dissolved in 30 ml. of dry benzene and then addedat 2025 to a mixture of 16 g. of N- methyl-N-B-picolylamine and 100 ml.of dry benzene. The reaction mixture is then stirred for one hour at 20,diluted with ether and shaken thoroughly with dilute hydrochloric acid.The acid solution is then treated With an excess of potassium carbonateand the oil which separates, extracted with ether. The ether solutionWas then dried and evaporated, yielding as the residue,IO-(N-methyl-Nfipicolyl-carbamoyl) dibenzo[a,d]cyclohepta[1,4,61trien-5-one, melting at 158-159".

Example 17 By replacement of the N-methyl-N-fi-picolyl-amine in theprocess of Example 16 with 12 g. of 4-hydroxyethylpiperazine there isobtained 10-[(4-hydroxyethyl-piperazinyl) carbonyl] dibenzo[a,d]cyclohepta[ 1,4,6] trien-5- one, the hydrochloride of which, uponrecrystallization from ethanol/ether, melts at 274-276".

Example 18 By the replacement of the N-methyl-N-B-picolyl-amine in theprocess of Example 16 with 20 g. of N-isopropyl- N-benzylamine there isobtained, as colorless crystals melting at 149150,10-(N-isopropyl-N-benzyl-carbamoyl)-dibenzo[a,d]cyclohepta[1,4,6]trien-5-one.

Example 19 A solution of 12 g. of 10-chlorocarbonyl-dibenzo[a,d]-cyclohepta[1,4,6]trien-5-one in 30 m1. of dry acetone is added dropwiseat 10-l5 to 200 ml. of concentrated aqueous ammonia solution.

The resultant precipitate is 10-carbamoyl-dibenzo[a,d]-cyclohepta[1,4,6]trien-5-one which melts, after recrystallization fromethanol/water, at 20921l.

Example 20 A solution of 10 g. of 10-chlorocarbonyl-dibenzo[a,d]-cyclohepta[l,4,6]trien-5-one in 30 ml. of dry benzene is added to amixture of 20 ml. of methylamine and 100 ml. of dry benzene. Thereaction mixture is then stirred for one hour at 20 and thereafterwashed With water, dilute hydrochloric acid, sodium carbonate solutionand lastly with water, dried and concentrated yielding as the residue,10 methyl carbamoyl dibenzo[a,d] cyclohepta[1,4,6]- trien-S-one whichmelts, after recrystallization from methanol/water, at 199-200".

1 7 Example 21 By the replacement of the methylamine in the process ofExample 20 with 10 g. of diethylamine there is obtained 10diethylcarbamoyl dibenzo[a,d]cyclohepta[1,4,6]- trien-S-one, which afterrecrystallization from high boiling petroleum ether, melts at 1l0-l12.

Example 22 9 g. of 10-carboxy-S,S-ethylenedioxy-dibenzo[a,d]cyclohepta[1,4,6]triene and 100 ml. of thionyl chloride are heated underreflux conditions for one hour. The excess thionyl chloride is thendistilled off under reduced pressure and the residual10-chlorocarbonyl-5,5-ethylenedi0xy-dibenzo[a,d]cyclohepta[1,4,6]trienedissolved in 50 ml. of dry benzene. The resultant solution is then addeddrop- Wise to a solution of 50 g. of dimethylamine in 300 ml. of drybenzene. During this addition, the temperature of the reaction mixtureis maintained at 20-25 by external cooling. After the addition, thereaction mixture is stirred for 30 minutes at 20 and then heated underreflux conditions for a further 30 minutes. The benzene and the excessdimethylamine are then distilled ofl under reduced pressure and theresidue taken up in benzene. The resultant solution is then washed Withwater, dilute hydrochloric acid, water, sodium bicarbonate solution andwater. It is then dried and concentrated, yielding as the residue,l-dimethylcarbamoyl 5,5ethylenedioxy-dibenzo[a,d]cyclohepta[1,4,6]triene which, afterrecrystallization from high boiling petroleum ether, melts at 204-205Example 23 A solution of g. of10-chlorocarbonyl-S-methylenedibenzo[a,d]cyclohepta[1,4,6]triene in 30ml. of dry benzene, is added dropwise to a solution of 20 ml. ofdimethylamine in 100 ml. of benzene. The reaction mixture is then workedup according to the procedure described in Example above, and theso-obtained crude l0-dimethylcarbamoyl 5methylenedibenzo[a,d]cyclohepta[l,4,6]- triene, after recrystallizationfrom ethylacetate/ petroleum ether, melts at 132-134".

The 10-chlorocarbonyl-S-methylene-dibenzo [a,d] cycloheptal[1,4,6]trieneemployed as the starting material above can be prepared as follows:

In a one liter round bottom flask equipped with a stirrer, droppingfunnel and reflux condenser, 5.4 g. of magnesium shavings are coveredover with ml. of dry ether and then, 2 ml. of a solution of g. of methyliodide in 100 ml. of ether is added thereto. As soon as the reaction hasstarted, the remainder of the methyl iodide solution is added dropwisein a manner so that the reaction mixture is maintained at a boilingstate. After the addition is completed, the reaction mixture is stirredfor one hour at 20 and then cooled to 40. A solution of 57 g. of10-bromo-dibenzo[a,d]cyclohepta[1,4,6]trien-S- one in 300 ml. of etheris then added, after which the whole reaction mixture is stirred for 20hours at 20.

The reaction mixture is then cooled with ice water and treated with acold saturated ammonium chloride solution. The organic layer isseparated and the aqueous phase extracted with 200 ml. of ether. Thecombined ether portions are then dried over sodium sulphate andconcentrated, yielding at a thick oily residue, S-hydroxy-5-methyl-10-bromo-dibenzo[a,d]cyclohepta[1,4,61triene.

30 g. of 5-hydroxy-5-methyl-10-bromo-dibenzo[a,d]cyclohepta[1,4,6]triene and 300 ml. of 3 percent ethanolic hydrochloricacid are heated on a steam bath under reflux conditions for 3 hours.Thereafter, the solution is concentrated under reduced pressure, theresidue taken up in ether and the ether solution washed with aqueoussodium bicarbonate solution and then with water, after which it is driedover sodium sulphate and concentrated. The residue is then distilled at0.03 mm. Hg and 160 and recrystallized from low boiling petroleum ether,yielding as colorless crystals, S-methylene-10-bromo-dibenzo[a,d]cyclohepta[1,4,6]-triene melting at 80-82".

In a one liter round bottom flask equipped with a stirrer, droppingfunnel and reflux condenser, a few drops of methyl iodide are added to4.5 g. of magnesium shavings. As soon as the reaction has started, asolution of 40 g. of S-methylene-IO-bromo-dibenzo[a,d]cyclohepta[1,4,6]triene in 200 ml. of dry, peroxide-free tetrahydrofuran is addeddropwise in such a manner that the temperature of the reaction mixtureis maintained between 50 and 55. After the addition is completed, thereaction mixture is heated under reflux conditions for three hours. Theresultant yellow brown solution is then cooled to 40 and anhydrouscarbon dioxide gas introduced. After two hours, the reaction terminates.The reaction mixture is then decomposed with a saturated ammoniumchloride solution. The tetrahydrofuran is evaporated 01f under reducedpressure and the residue is extracted with ether. The ether solution isthen shaken up with dilute sodium carbonate solution and the so-obtainedalkaline solution acidified with hydrochloric acid whereupon thereaction product precipitates. The precipitated product is taken up inether, the ether solution washed, dried and evaporated, yielding as theresidue S-methylene-IO-carboxyl-dibenzo- [a,d] cycloheptal[1,4,61triene,which after recrystallization from ethyl acetate/ petroleum ether, meltsat 210-212.

The so-obtained S-methylene-10-carboxy-dibenzo[a,d]cycloheptal[1,4,6]triene is then converted to S-methylene- 10-chlorocarbonyldibenzo [a,d] cyclohepta 1,4,6] triene 5- one according to thechlorination procedure described in Example 15 above.

Example 24 A solution of 10 g. of 10-chlorocarbonyl-dibenzo [a,d]cyclohepta[1,4,6]triene-5-one in 30 ml. of dry benzene is added dropwiseto a solution of 10 g. of morpholine in ml. of benzene. The reactionmixture is then worked up according to the procedure given in Example 15above, yielding 10-morpholinocarbonyl-dibenzo[a,d]cyclohepta[1,4,6]triene-5-one which, after recrystallization from benzene/petroleum ether, melts at 15 5-15 6".

Example 25 7 g. of 10-carbomethoxy-dibenzo[a,d]cyclohepta[1,4,6]trien-5-one and 30 m1. of 30 percent methanolic dimethylamine solutionare heated for three hours at 100 in a sealed tube. The residue obtainedafter the evaporation of the methanol is 10-dimethylcarbamoyl-dibenzo-[a.d]cyclohepta[1,4,6]trien-5-one which, after recrystallization fromhigh boiling petroleum ether, melts, at 146- 147.

The 10 carbomethoxy-dibenzo [a,d]cyclohepta[1,4,6] trien-S-one used asthe starting material above can be prepared as follows:

10 g. of 10-chlorocarbonyl-dibenzo[a,d]cyclohepta- [1,4,6]trien-5-one isdissolved in 40 ml. of dry acetone and the solution is then addeddropwise with stirring to 200 ml. of methanol. The whole reactionmixture is then briefly heated to boiling, after which the methanol isevaporated off and the residue taken up in ether, The ether solution isthen Washed, dried and evaporated, yielding 10carbomethoxy-dibenzo[a,d]cyclohepta[1,4,6]trien-5-one which, afterrecrystallization from high boiling petroleum ether melts at 112-114".

Example 26 In a 500 ml. roound bottom flask equipped with stirrer,dropping funnel and reflux condenser, 1.25 g. of magnesium shavings arecovered over with 10 ml. of dry ether and with 1 ml. of a solution of7.16 g. of methyl iodide in 25 ml. of ether. As soon as the reaction hasstarted, the remainder of the methyl iodide solution is added dropwisein such a manner that the reaction mixture is maintained at a boilingstate. The reaction mixture is then stirred for one hour at 20 and then,after the addition of a solution of 13.8 g. ofIO-dimethylcarbamoyldibenzo[a,d]cyclohepta[1,4,61trien-5-one and 75 ml.of

dry ether, stirred for a further three hours at 20.

The reaction mixture is then cooled with ice water and treated with acold saturated ammonium chloride solution. The aqueous phase isseparated from the organic layer and extracted with 100 ml. of ether.The combined ether portions are then dried over sodium sulphate andevaporated, yielding as the residue 10-dimethylcarbamoyl-S-hydroxy-S-methyl-dibenzo[a,d]cyclohepta[ 1,4,6]triene which, afterrecrystallization from ethyl acetate/ petroleum ether, melts at 200202.

g. of-dimethylcarbamoyl-5-hydroxy-5-methyl-dibenzo[a,d]cyclohepta[1,4,6]trieneand 50 ml. of one percent ethanolic hydrochloric acid solution areheated under reflux conditions for one hour on a steam bath. After thesolution is concentrated under reduced pressure, the residue is taken upin methylene chloride and the methylene chloride solution washed withaqueous sodium carbonate and with water, dried over sodium sulphate andevaporated. There is thus obtained 10-dimethyl-carbamoyl-S- methylenedibenzo[a,d]cyclohepta[1,4,6]triene which,

after recrystallization from ethyl acetate/ petroleum ether,

melts at 132-134.

Example 27 g. of polyvinylpyrrolidone (K average molecular weight ofabout 40000) is dissolved in 120 g. of isopropanol. To this solutionthere is then added with stirring, a mixture of 100 g. of10-dimethylcarbamoyl-dibenzo[a,d]cyclohepta[1,4,6]triene-5-one, 500 g.of lactose and 300 g. of corn starch. The moist mass is then passedthrought a suitable sieve and dried in a ventilated dryer at about 60.The dried granulation is then mixed with 25 g. of corn starch, g. oftalc and 10 g. of magnesium stearate. From the so-obtained thoroughlyintermixed granulation, there are pressed drages weighing 112 mg. eachwith an active ingredient content of 10 mg., or weighing 280 mg. eachwith an active ingredient content of 25 mg. Subsequently, the pressedtablets can be coated with a concentrated sugar syrup according toconventional pharmaceutical methodology.

Example 28 3 .5 g. 10(11)-carboxy-3-chloro-dibenzo[a,d]cyclohepta[1,4,6]trien-5-one and 30 ml. of thionyl chloride were reacted togetherfor 1 hour at reflux. The excess thionyl chloride was thereafter removedby distillation at reduced pressure. The resulting10-chloro-carbonyl-3-chloro-dibenzo[a,d]cyclohepta[l,4,6]trien-5-one isdissolved in 20 ml. of dry benzene and added dropwise to a solutioncontaining 20 g. of dimethylamine in 100 ml. of benzene. The reactiontemperature is maintained at 2025 through outside cooling. The reactionmixture is thereafter heated for another hour at 20 and then the benzeneand the excess amine are removed by distillation at reduced pressure.The residue is taken up in benzene. The resulting solution is washedwith water, dilute HCl, water, sodium carbonate solution, again withWater, dried and evaporated. The resulting 10(11) dimethyl carbamoyl3-chloro-dibenzo [a,d] cyclohepta[1,4,6]trien 5 one afterrecrystallization from benzene/ petroleum ether has a melting point of126- 128.

The 10(11) carboxyl-3-chloro-dibenzo [a,d] cyclohepta [1,4,6]trien-5-oneutilized as a starting material can be prepared, for example, asfollows:

64 g. of 3-chloro-dibenzo[a,d]cyclohepta[1,4,6]trien-5- one is dissolvedin 550 ml. of chloroform and thereafter treated with 13.88 ml. ofbromine. The brown color disappears instantaneously. After reaction iscompleted, the solution is evaporated under reduced pressure and theresidue is dissolved in benzene to yield3-chloro-l0,11-dibromo-dibenzo[a,d]cyclohepta[1,4]dien-5-one having amelting point of 172-l74.

76.6 g. of 3-chloro-10,1l-dibromo-dibenzo[a,d]cyclohepta[1,4]dien-5-onedissolved in 800 ml. of ethanol and 11.48 g. of potassium hydroxidedissolved in 20 ml. of water are reacted together for 3 hours underreflux. The ethanol is removed by distillation under reduced pressure,

and the residue is taken up in chloroform. The chloroform solution iswashed neutral with water, dried over sodium sulfate and evaporated.Through fractional crystallization from benzene and then from ethanol,two isomers of 3 chloro 10(l1)bromo dibenzo[a,d]cyclohepta[1,4,6]trien-5-one are obtained, the a-isomer has a melting point of 178179 andthe ,8-isomer has a melting point of 129- 132.

A mixture containing 63 g. of3-chloro-10(11)bromodibenzo[a,d]cyclohepta[1,4,61trien-5-one, 250 ml. ofethylene glycol and 0.75 g. of p-toluenesulfonic acid are warmedtogether with vigorous stirring on a water bath at 200". Then at apressure of 30 mm./Hg 200 ml. of ethylene glycol are distilled over a 2/2-hour period.

The cooled residue is treated with 50 ml. of a 12 percent solution ofcaustic soda and 30 ml. of water. The product is filtered, washed withwater and recrystallized from ethanol to yield10(11)bromo-3-chloro-5,5-ethylenedioxy-dibenzo[a,d]cyclohepta[1,4,61trienehaving a melting point of 182. In a 250 ml. 3-nccked flask equipped witha stirrer, dropping device and reflux condenser, 2.25 g. of magnesiumchips are treated with 2 drops of methyl iodide and as soon as thereaction starts, a solution containing 21.1 g. of10(11)bromo-3-chloro-5,5-ethylenedioxy-dibenzo[a,d]cyclohepta[1,4,6]trienein 125 ml. of peroxide free tetrahydrofuran is added dropwise and thetemperature is maintained at 60. Thereafter, the reaction mixture isreacted for 3 hours under reflux conditions whereby the magnesium chipsdisappear. Then, the brown solution is treated with a stream of drycarbonic acid at 40. After 2 hours, the reaction mixture through theaddition of dilute hydrochloric acid is decomposed and theterahydrofuran is evaporated under reduced pressure. The residue isextracted with ethyl acetate and the Solution is taken up with sodiumcarbonate solution. After acidification of the alkaline solution withhydrochloric acid, the 10(11)carboxy 3-chloro-5,S-ethylenedioxy-dibenzo[a,d]cyclohepta [1,4,6]triene precipitates and after recrystallizationfrom ethanol/water has a melting point of 300.

4.4 g. of10(11)carboxy-3-chloro-5,S-ethylenedioxy-dibenzo[a,d]cyclohepta[1,4,6]triene,200 ml. of acetone and 30 ml. of concentrated hydrochloric acid areheated together for 1 hour under reflux conditions. After removal of thesolvent, the residue is dissolved in an aqueous sodium carbonatesolution. This solution is filtered and acidified with hydrochloricacid. The precipitated product, 10(11)carboxy 3chloro'dibenzo[a,d]cyclohepta[1,4,6] trien-S-one, afterrecrystallization from methanol has a melting point of 207209.

Example 29 8 g. of 5-hydroxy-5-(3'-methoxy-pr0pyl)-dibenzo[a,d]cyclohepta[1,4,6]trien-lO-carboxylic acid dimethylamide, ml. of absolutealcohol and 8ml. of a 20 percent solution of hydrochloric acid inethanol were warmed on a water bath under reflux conditions for 3 hours.The solution was evaporated to dryness under reduced pressure. Theresidual 5-(3'-methoxy-propylidene) dibenzo[a,d]cyclohepta[1,4,6]trien-lO-carboxylic acid dimethylamide afterrecrystallization from aqueous methanol has a melting point of 102-103".

The 5 hydroxy-S-(3'-methoxy-propyl)dibenzo[a,d]cyclohepta[1,4,6]trien 10carboxylic acid dimethylamide utilized as a starting material can beprepared as follows:

57 g. of 10-bromo-dibenzo[a,d]cyclohepta[l,4,6]trien- S-one, 36 g.copper cyanide and 200 ml. dimethylformamide are heated together underreflux conditions for 5 hours. After the solvent is removed bydistillation under reduced pressure, the residue is taken up inmethylene chloride. The methylene chloride solution is washed withwater, dried and evaporated. The residual 10-cyano-dibenzo[a,d]cyclohepta[1,4,6]trien-5-one after recrystallization from ethanolhas a melting point of 174-175.

9.24 g. of 10-cyano dibromo[a,d]cyclohepta[1,4,6] trien-S-one in 10 ml.of ethanol and 3.2 ml. of 3 N caustic soda are treated dropwise with 16ml. of 30 percent of hydrogen peroxide. The temperature is maintainedbelow 50 through cooling. The reaction mixture is heated at 50 for 3hours and thereafter evaporated. The residue is extracted with methylenechloride and the extract is shaken with sodium carbonate. Thereafter,the alkaline solution is acidified with hydrochloric acid andIO-carboxy-dibenzo[a,d1cyclohepta[1,4,6]trien one precipitates. Afterrecrystallization from ethyl acetate/ petroleum ether, the product has amelting point of 20l-203.

12.5 g. of carboxy-dibenzo[a,d]cyc1ohepta[1,4,6] trien-S-one and 40 ml.of thionyl chloride are reacted together for 1 hour under refluxconditions. Thereafter, the excess thionyl chloride is removed undervacuum distillation whereby 10-chloro-carbonyl-dibenzo[a,d]cyclohepta[1,4,6]trien-5-one remains behind.

T o a solution containing 10 g. of dimethylamine in 100 ml. of drybenzene is added dropwise a solution containing 12.6 g. of10-chloro-carbonyl-dibenzo[a,d] cyclohepta[1,4,6]trien-5-one in 50 ml.of dry benzene with stirring. The reaction temperature is maintained at25 through external cooling. Thereafter, the reaction mixture is heatedfor minutes under reflux conditions. Then, the benzene and the excessamine are removed by distillation under reduced pressure. The residue istaken up in benzene and the solution is Washed with water, dilutehydrochloric acid, water, sodium bicarbonate solution and again withwater, dried and evaporated. The resultingdibenzo[a,d]cyclohepta[1,4,6]trien-S-one-IO-carbOxylic aciddimethylamide after recrystallization from petroleum ether has a meltingpoint of 146-147".

In a 500 ml. 3-necked flask equipped with stirrer, dropping device andammonia condenser, 100 ml. of liquid ammonia are dried through theintroduction of sodium chips until the appearance of stable blue color.Thereafter, 1.4 g. of sodium are introduced in small portions and themixture is stirred over a 15-minute period. The resulting blue solutionis treated dropwise with 4.5 g. of methyl propargyl ether, heated for 2hours whereby the blue color disappears. The solution is stirred afterthe portionwise addition of 16.6 g. ofdibenzo[a,d]cyclohepta[1,4,6]trien- 5-one-10-carboxylic aciddimethylamide and heated for a period of 5 hours. Then it is treatedwith 6 g. of ammonium chloride and taken up with 100 ml. of ether. Theammonia is removed by distillation overnight. The following day thereaction mixture is shaken out with water. The ether is removed anddried. After the evaporation of the ether, the remaining S-hydroxy 5(3'-methoxy-propinyl) dibenzo[a,d]cyclohepta[1,4,6]triene 10 carboxylicacid dimethylamide is further purified by the following procedure:

13.1 g. of 5-hydroxy-5-(3'-methoxy-propinyl)-dibenzo-[a,d]cyclohepta[1,4,6]triene-lO-carboxylic acid dimethylamide ishydrogenated in 250 ml. of isopropanol in the presence of platinum oxideunder normal pressure and at room temperature. Following thehydrogenation, the solution is filtered to remove the catalyst. Afterremoval of the isopropanol by distillation and recrystallization fromethyl acetate/petroleum ether, the 5-hydroxy-5-(3'-methoxy-propyl)dibenzo[a,d]cyclohepta[1,4,6]triene l0 carboxylic acid dimethylamide hasa melting point of 183485".

In an analogous manner through dehydrogenation, the following can beprepared:

From 5-hydroxy 5 (3-methoxy propyl) dibenzo[a,d]cyclohepta[1,4,6]trien-lO-carboxylic acid N-methyl- N- B-picolyl)-amide,

The 5-(3-methoxy-propylidene) dibenzo[a,d]cyclohepta[1,4,61trien 10 Nmethyl-N-(fl-picolyD-amide, melting point 103-10 5;

From 5-hydroxy-5-(3-methoxy propyl) 10 [4'-(2"- hydroxyethyl) piperazinocarbonyl] dibenzo[a,d]cyclohepta[1,4,6]triene,

The 5-(3-methoxy propylidene) l0 [4'-(2-hydroxy-ethyl)-piperazinocarbonyl] dibenzo [a,d] cyclohepta[1,4,6]triene, melting point 210-213;

From 5-hydroxy-5-(3 methoxy propyl) dibenzo [a,d]cyclohepta[1,4,6]triene10 carboxylic acid-(2'- dimethylamino-ethylamide) The 5-(3'-methoxypropylidene) dibenzo[a,d]cyclohepta[1,4,61triene 10 carboxylicacid-(2-dimethylamino-ethylamide), melting point 118119 C.;

From S-hydroxy 5 (3 methoxy propyl)-dibenzo [a,d]cyclohepta[l,4,6]trien10 carboxylic acid-N,N- dimethylamidine-hydrochloride,

The 5-(3' methoxy propylidene) dibenzo[a,d]cyclohepta[1,4,61triene 10carboxylic acid N,N-dimethylamidine hydrochloride, melting point290-291;

From S-hydroxy 5 (3-methoxy propyl)-dibenzo [a,d]cyclohepta[l,4,6]trienel0 carboxylic acid-N- methyl-N-benzylamide,

The 5-(3'-methoxy propylidene) dibenzo[a,d]cyclohepta[1,4,61triene 10carboxylic acid-N-methyl-N- benzylamide, melting point 124-126";

From 5-hydroxy-5-(3-rnethoxy propyl)-dibenzo[a,d1 cyclohepta[1,4,6]triene-lO-cahboxylic acid-diethylamide,

The 5-(3'-methoxy propylidene)dibenzo[a,d]cyclohepta[1,4,6]trien-lO-carboxylic acid diethylamide,melting point 118l20;

From 5 hydroxy-5-(3'-chloro propyl)-dibenzo[a,d1 cyclohepta[ 1,4,6triene- IO-carboxylic acid-dimethylamide,

The 5-(3'-chloro propylidene) dibenzo[a,d]cyclohepta[1,4,61triene 10carboxylic acid-dimet-hylamide, melting point 141143;

From 5-hydroxy-5-(3'-ethoxy propyl) dibenzo[a,d1 cyclohepta[ 1,4,6triene10-carboxylic acid-dimethylamide,

The 5- (3 '-ethoxy-propylidene -dibenzo [a,d] cyclohepta-[1,4,6]trien-10-carboxylic acid dimethylarnide, melting point 123124;

From 5-hydroxy-5-(3-methoxy propyl)-dibenzo[a,d]cyclohepta[1,4,6]triene-lO-carboxylic acid amide,

The 5-(3'-methoxy propylidene) dibenzo[a,d1cyclohepta[1,4,6]triene-lO-carboxylic acid-amide, melting point 164-166;and

From 5-hydroxy-5-(3'-methoxy propyl)-dibenzo[a,d1 cyclohepta[ 1,4,6]trienel O-carboxylic acid-methylamide,

The 5-(3'-methoxypropylidene)-dibenzo[a,d]cyclohepta[1,4,6]triene-10-carboxy-methylamide,melting point 178180.

Example 30 10 g. of IO-carboxy dibenzo[a,d]cyclohepta[l,4,6]triene-S-one and 50 ml. of thionyl chloride are boiled together 1 hourunder reflux conditions. The residual thionyl chloride is distilled offunder reduced pressure. The 10 chlorocarbonyldibenzo[a,d]cyclohepta[1,4,6] trien-S-one obtained is dissolved in 40ml. of dried benzene and added dropwise to a solution of 10 g. ofpyrrolidine in ml. of dry benzene. The reaction temperature is kept at20 to 25 C. by external cooling. The reaction mixture is afterwardsstirred 30 minutes at 20 C., washed with water, dilute hydrochloricacid, water, sodium carbonate solution and again with water, dried andevaporated to dryness. The remaining10-pyrrolidinocarbonyl-dibenzo[a,d]cyclohepta[1,4,6]triene 5 -one melts,after recrystallization from acetic ester/petroleum ether, at 142-143 C.

Example 31 The crude 10-ch1orocarbonyl dibenzo [a,d]cyclohepta[1,4,6]triene-5-one obtained from 10 g. of10-carboxydibenzo[a,d1cyclohepta[1,4,6]triene-5-one is dissolved in 50ml. of dry benzene and added drop by drop to a solution of 10 g. of2-methyl-piperidine in 100 ml. of benzene. The reaction temperature iskept at about 20 C. by external cooling. The reaction mixture isthereafter stirred for a further 30 minutes at 20 C., washed with water,dilute hydrochloric acid, Water, sodium carbonate solution and againwith water, dried over sodium sulphate and evaporated to dryness. Theresidual IO-(Z-methyl-piperidino)-carbonyl dibenzo[a,d]cyclohepta[1,4,6]triene-5- 23 one melts, after recrystallization fromacetic ester/petroleum ether at 125l27 C.

We claim: 1. A compound selected from the group consisting of compoundsof the formula:

wherein X is oxygen; R and R are each independently selected from thegroup consisting of hydrogen and halogen; Z is =CHCH CH B wherein B isselected from the group consisting of halogen and lower alkoxy of 1-4carbon atoms; and P and Q are each independently selected from the groupconsisting of hydrogen, lower alkyl of l-4 carbon atoms, benzyl,flpicolyl and dilower alkylamino-lower alkyl, the alkyl groups of whicheach are of 1-4 carbon atoms; and P and Q taken together with the N atomare selected from the group consisting of piperidino, lower alkylpiper-24 idino having 1-4 carbon atoms in the lower alkyl moiety, piperazino,pyrrolidino, morpholino, N -hydroxy-lower alkylpiperazino having l-4carbon atoms in the lower alkyl moiety and 4-(4"-chlorobenzyl)-piperazino, and pharmaceutically acceptable acid addition salts thereof.

2. A compound in accordance with claim 1, wherein R and R are hydrogen.

3. A compound in accordance with claim 2, wherein P and Q are loweralkyl of 1-4 carbon atoms.

4. A compound in accordance with claim 1, i.e., 5-(3- methoxypropylidene) dibenzo[a,d]cyclohepta[1,4,6] triene-lO-carboxylic aciddimethylamide.

5. A compound in accordance with claim 1, wherein R is hydrogen and R ishalogen.

No references cited.

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner US. Cl. X.R.

260-247.7 F, 268 TR, 294.7 C, 326.3, 340.9, 514 R, 520, 558 R; 424-324

